Regulatory Challenges
Preclinical studies for intranasal and pulmonary programs are governed by stringent regulatory frameworks. In the United States, these studies must comply with 21 CFR Part 58.1: Good Laboratory Practice for Nonclinical Laboratory Studies, which outlines the conduct, personnel, protocols, and quality oversight requirements.
Similarly, the European Union has its own set of guidelines. However, the diversity of devices used for inhalation and the need to adapt these devices for animal studies pose significant challenges. Engaging with experts and regulators early in the process is crucial to ensure the selection of appropriate species and devices for the studies.
Approaches to Formulation
Formulating drugs for nasal and pulmonary delivery involves several key considerations. For aqueous nasal sprays, factors such as the active pharmaceutical ingredient (API), its solubility, choice of excipients, pH, and osmolarity are critical
Targeting specific areas within the nasal cavity, such as the olfactory region for central nervous system (CNS) delivery, is also important. Enhancements like mucoadhesives and permeation enhancers can improve retention and absorption
Powder formulations are gaining interest, especially for sensitive molecules that cannot be stored at room temperature. The development process for powders involves determining the physical and chemical characteristics of the API, followed by particle engineering and processing to produce particles of an appropriate size for nasal delivery. The choice of formulation—whether liquid or powder—affects the stability and delivery efficacy in both animal and human studies.
Overview of Studies Conducted
Preclinical studies often use a variety of animal models, ranging from small animals like mice and rats to larger species such as dogs and non-human primates (NHPs). The selection of an animal model depends on the specifics of the program, such as targeting CNS delivery or systemic delivery via pulmonary or intranasal routes. For instance, studies have shown that using Aptar Pharma delivery systems, different formulations of sumatriptan (a nasal spray, a dry powder, and a nasal spray with a permeation enhancer) were evaluated in NHPs to understand their pharmacokinetics and bioavailability.
Pulmonary dosing studies often involve generating an aerosol atmosphere containing the test article and estimating the dose delivered to animals using generalised deposition fractions and allometric relations for respiratory rates.
Techniques like intratracheal instillation for liquids or insufflation for powders can bypass nasal airways to maximise pulmonary doses.
Advantages of Fine Mist Sprayer Devices
Fine Mist sprayer devices offer several advantages for preclinical studies. They are particularly useful for administering nasal formulations in animal models, especially when human devices are not compatible with smaller animals. For example, a study comparing the Aptar Fine Mist Sprayer with a pipette in delivering a nasal exosome formulation showed no significant differences in the uptake of the formulation into the brain, indicating the effectiveness of the fine mist sprayer. The fine mist sprayer was also easier to use and did not experience issues with clogging when used with true solutions.
In conclusion, optimizing preclinical studies for intranasal and pulmonary programs involves navigating regulatory challenges, carefully considering formulation approaches, selecting appropriate animal models, and leveraging the advantages of Fine Mist sprayer devices. These efforts are essential to ensure the safety and efficacy of new drug candidates, paving the way for successful clinical trials and ultimately, effective treatments for patients.
